The purpose of this proposal is to gain insight into the basic mechanisms underlying human neurodegenerative disease using Drosophila as a readily accessible model system. The subject of the present application is a Drosophila mutant called swiss-cheese (sws). SWS shows progressive degeneration of the adult nervous system. SWS is the functional ortholog of human Neuropathy Target Esterase (NTE), the apparent molecular target in organophosphate-induced delayed neuropathy (OPIDN). OPIDN is a distal axonopathy similar to a large number of other peripheral neuropathies associated with age-related, genetic, metabolic and toxic conditions. In addition, recent data suggest that, a neuronal specific knock-out of NTE in mice also causes neurodegeneration. Although NTE has been studied for 20 years and as many as 500,000 cases of organophosphate (OP) poisoning through pesticides or nerve agents occur each year, nothing is known about the biological function of this important protein. Therefore, this project aims to further characterize SWS and determine the role it plays in neurodegeneration and axonopathy. Drosophila reveals the neurodegenerative phenotype and provides an easy accessible model system. Especially genetic studies using mice are not easy feasible and yeast and Caenorhabditis elegans knock-outs do not reveal a phenotype. The studies outlined in this proposal focus on the identification and characterization of protein domains and the biological substrate. addition, the pathways in which SWS functions will be elucidated by molecular and genetic approaches (creation and functional analysis of flies expressing different constructs, two-hybrid screens and genetic interaction screens). The functional analysis will eventually lead to an understanding of the physiological function of SWS and why it is required to prevent axonal degeneration and neural cell death. An insight into the normal function of SWS can then help to better plan future studies to understand the involvement of NTE in OP toxicity and OPIDN in humans.